Abstract:
:Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyzed fibrotic capsules surrounding surgically excised human breast implants from 12 individuals. We found increased numbers of interleukin 17 (IL17)-producing γδ+ T cells and CD4+ T helper 17 (TH17) cells as well as senescent stromal cells in the fibrotic capsules. Further analysis in a murine model demonstrated an early innate IL17 response to implanted synthetic material (polycaprolactone) particles that was mediated by innate lymphoid cells and γδ+ T cells. This was followed by a chronic adaptive CD4+ TH17 cell response that was antigen dependent. Synthetic materials with varying chemical and physical properties implanted either in injured muscle or subcutaneously induced similar IL17 responses in mice. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to implanted synthetic materials and the development of p16INK4a senescent cells. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model. Discovery of a feed-forward loop between the TH17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Chung L,Maestas DR Jr,Lebid A,Mageau A,Rosson GD,Wu X,Wolf MT,Tam AJ,Vanderzee I,Wang X,Andorko JI,Zhang H,Narain R,Sadtler K,Fan H,Čiháková D,Le Saux CJ,Housseau F,Pardoll DM,Elisseeff JHdoi
10.1126/scitranslmed.aax3799subject
Has Abstractpub_date
2020-04-15 00:00:00issue
539eissn
1946-6234issn
1946-6242pii
12/539/eaax3799journal_volume
12pub_type
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